(S)-(+)-(2-chlorophenyl)-2-(6,7-dihydro-4H-thieno[3,2-c]pyridine-5-yl-acetate hydrogensuifate is a known platelet aggregation inhibitor drug, having INN clopidogrel hydrogensulfate.
Clopidogrel hydrogensulfate is described first in European Patent Specification No. 281 459. Hungarian equivalent of this patent is Hungarian patent No. 197 909.
The product is characterized by its melting point and optical rotation, which are 182° C. and [α]D20=+51.61 (c=2.044 g/100 ml, methanol) respectively. Crystal form of the product is not mentioned.
Polymorph forms of clopidogrel hydrogensulfate are described first in the French Patent Application No. 98/07464. Polymorph form 1 is specified as a monocline crystal form, characterized by X-ray diffraction pattern and infrared spectrum.
Melting point and the optical rotation of the form 1 are 184° C. and [α]D20=+55.1° (c=1.891/100 ml, methanol respectively. On the basis of these data, authors state that the polymorph form described in the European patent specification No. 281 459 is identical to polymorph form 1. The orthorhombic polymorph form 2 is characterized by its melting point of 176° C. in the specification of French Patent Application No. 98/07464.
Polymorph form 1 is prepared according to cited specification by dissolving clopidogrel base in acetone and adding 80% sulfuric acid in an equimolecular amount to the solution at 20° C. The solvent is evaporated partly, the residue is cooled to 0-5° C. and the precipitate is filtered.
Polymorph form 2 is precipitated out of the filtrate, which is obtained in the process of the preparation of polymorph form 1 and stored for 3-6 months below 40° C.
According to this patent specification, polymorph form 2 can also be prepared by adding equimolar amount of 80% sulfuric acid to a solution of clopidogrel base in acetone at 20° C. without or in the presence of seeding crystals. Subsequently the reaction mixture is boiled for two hours, the solvent is evaporated partly, the residue is cooled to −5° C., and either the precipitated product is filtered, or seeding crystals are added, the reaction mixture is stirred at 20° C., then the product is filtered.
According to the specification of the International Patent Application No. 02/059128, polymorph form 1 of clopiodogrel hydrogensulfate is prepared by the reaction of the solution of clopidogrel sulfate in threefold amount of acetone calculated based on the amount of clopidogrel base with concentrated sulfuric acid between 0-5° C. After addition of sulfuric acid, one more part of acetone is added, then the reaction mixture is stirred for 4 hours. Then polymorph form 1 is isolated with a melting point of 185° C.
According to the specification of International Patent Application No. 03/051362, amorphous form or several polymorph forms of clopidogrel hydrogensulfate are obtained by recrystallisation of clopidogrel hydrogensulfate using different solvents, or by the precipitation with anti-solvents from its solutions.
Amorphous clopidogrel hydrogensulfate is prepared according to International Patent Application No. 03/051362 by dissolution of clopidogrel hydrogen sulfate in methanol or ethanol, then to the obtained solution are diethyl ether or methyl tert-butyl ether added, the solubility of clopidogrel hydrogensulfate is reduced in the mixture and clopidogrel hydrogensulfate is precipitated out of the solution in amorphous form.
In another case, solution of clopidogrel hydrogensulfate in ethanol is added to boiling toluene, then the solution is cooled, yielding the amorphous product. The disadvantage of this process is the use of toluene being an aromatic solvent which is avoidable in the synthesis of a pharmaceutical drug, especially in the last step of the process.
In case of using an ether type solvent to precipitate out the product from its solution prepared in an alcohol or acetone, polymorph form 1 or amorphous form is formed according to the reaction conditions.
Moreover, the mixture of the amorphous and polymorph form 1 can be produced as well. In presence of ether type solvents, the amorphous product can be converted into polymorph form 1. Examples of the International Patent specification No. 03/051362 demonstrate the strong tendency of clopidogrel hydrogensulfate to crystallise.
Data summarised in the Table 1 demonstrate that the precipitation of clopidogrel hydrogensulfate results in different crystalline polymorph forms.
TABLE 1SolventAntisolventMorphologyAcetonitrileDEEPolymorph form 2methanolDEEAmorphousethanolMTBE or DEEPolymorph form 1methanolMTBE or DEEPolymorph form 1ethanolMTBEPolymorph form 1 + AmorphousmethanolDEEPolymorph form 12-butanolMTBEPolymorph form 5DEE: diethyl etherMTBE: methyl-tert.-butyl ether
According to the Table 2, further polymorph forms are formed by triturating the evaporated residue of a solution of clopidogrel hydrogensulfate with solvents in which the solubility of clopidogrel hydrogen sulfate is very low or the product is immiscible with.
TABLE 2Solvent used forSolutiontriturationMorphology1-butanolDEE or MTBEPolymorph form 32-butanolDEE or MTBEPolymorph form 51-propanolMTBEPolymorph form 6Acetone—AmorphousDEE: diethyl etherMTBE: methyl-tert.-butyl ether
The polymorph forms of the evaporated residues before the trituration are not mentioned in the specification. Although the amorphous form of clopidogrel hydrogensulfate can be produced by evaporation of the solution of clopidogrel hydrogensulfate in acetone to dryness, the process can not be accomplished easily on industrial scale.
It can not be predicted whether the amorphous product obtained after trituration in a suitable solvent remains amorphous form, since it may easily transform into different polymorphous forms spontaneously, for example into polymorph form 1.
According to the examples above, it is impossible to predict which polymorph form will be precipitated or transformed into other form by the interaction of clopidogrel hydrogensulfate and a selected solvent.
It is very important that the amorphous form can be changed into polymorph form 1 by triturating with ethers. In the same process, the trituration with ether results the polymorph form 2, while in other cases, polymorph forms depicted in Table 2 are formed.
Official requirements defined in Pharmacopoeias are ever increasing with regard to the purity and morphological uniformity of pharmaceutical active ingredients. Requirements towards morphological uniformity of a substance are justified by the fact that biological availabilities of different polymorph forms may be different.
According to the International Patent Application No 02/59087, the solubility and the biological availability of the amorphous form of the active agent having INN name atorvastatine calcium is better then its morphologically uniform crystalline forms.
Properties of different polymorph forms may be different from the pharmaceutical technology point of view. The use of amorphous form can be advantageous either from the economical or the technological point of view as well.